ABSTRACT
The demonstrated activity of irinotecan, oxaliplatin, raltitrexed, and the oral 5-fluorouracil (5-FU) prodrugs (discussed in detail elsewhere in this book) has shifted much attention from the field of biochemical modulation of 5-FU to that of combination chemotherapy for colorectal cancer in the last few years. This general paradigm appears justified on the basis of clinical reports1,2 suggesting higher response rates, longer progression-free survival, and in some cases prolonged survival for the combinations compared with 5-FU alone. Nevertheless, most of the positive combination studies have used complex scheduling of modulated 5-FU as backbone for the combination. In addition, combination regimens with the new agents are more toxic than modulated 5-FU alone, and the overall improvement of efficacy parameters remains limited. Furthermore, it must be remembered that, although appealing for their convenient administration route, the new oral fluoropyrimidines require conversion to 5-FU to exert their cytotoxic effects. These three reasons, coupled with the strong and active interest in determining the molecular factors predictive for response to 5-FU, have maintained and renewed interest in the pharmacology of the fluoropyrimidines.
